Recently, we identified two- and three-variant combinations associated with a particular increase of bladder cancer risk in a urinary bladder cancer case-control series (Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), 1501 cases, 1565 controls). In an independent case-control series (Nijmegen Bladder Cancer Study, NBCS, 1468 cases, 1720 controls) we confirmed these two- and three-variant combinations. Pooled analysis of the two studies as discovery group (IfADo-NBCS) resulted in sufficient statistical power to test up to four-variant combinations by a logistic regression approach. The New England and Spanish Bladder Cancer Studies (2080 cases and 2167 controls) were used as a replication series. Twelve previously identified risk variants were considered.

In conclusion, we show that four high-risk variants can statistically interact to confer increased bladder cancer risk particularly in never smokers.

Funding: KI's work has been supported by Deutsche Forschungsgemeinschaft (DFG) within the Collaborative Research Center SFB 876 "Providing Information by Resource-Constrained Analysis", project C4. The NBS (source of controls) and the NBCS (source of the cases) were funded by the Radboud university medical center. This work was supported by the Intramural Research Program of the National Institutes of Health and the Division of Cancer Epidemiology and Genetics, National Cancer Institute (Z01 CP010187-13).